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The Serotonin Signaling System: From Basic Understanding To Drug Development for Functional GI Disorders

  • Michael D. Gershon
    Correspondence
    Address requests for reprints to: Michael D. Gershon, MD, Department of Pathology & Cell Biology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. fax: (212) 305-3970.
    Affiliations
    Department of Pathology & Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York
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  • Jan Tack
    Affiliations
    Section of Gastroenterology, Catholic University of Leuven, Gastro-enterologie, O & N, Leuven, Belgium
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      Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT4 partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT3 antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT1 agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders.

      Abbreviations used in this paper:

      EC (enterochromaffin), IPANs (intrinsic primary afferent neurons), SSRIs (selective serotonin reuptake inhibitors), TpH (tryptophan hydroxylase)
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